This application is a 371 of PCT/EP00/00746 filed Jan. 31, 2000.
The present invention relates in general to the field of cancer treatment and, more particularly, provides an anti-tumor composition comprising an alkylating anthracycline and an anti-mitotic compound and/or a platinum derivative, having a synergistic or additive anti-neoplastic effect. The present invention provides, in a first aspect, a pharmaceutical composition for use in anti-neoplastic therapy in mammals, including humans, comprising
an anthracycline of formula Ia or Ib 
an anti-neoplastic anti-mitotic compound and/or a platinum derivative, and a pharmaceutically acceptable carrier or excipient.
The chemical names of the anthracyclines of formula Ia and Ib are 4-demethoxy-3xe2x80x2-deamino-3xe2x80x2-aziridinyl-4xe2x80x2-methansulfonyl daunorubicin (Ia) and 4-demethoxy-N,N-bis(2-chloroethyl)-4xe2x80x2-methansulfonyl daunorubicin (Ib). These anthracyclines were described in Anticancer Drug Design (1995), vol. 10, 641-653, and claimed respectively in U.S. Pat. No. 5,532,218 and U.S. Pat. No. 5,496,800. Both compounds intercalate into DNA via the chromophore and alkylate guanine at Nxe2x88x92 position in DNA minor groove via their reactive moiety on position 3xe2x80x2 of the amino sugar. Compounds Ia and Ib are able to circumvent the resistance to all major classes of cytotoxics, indicating that the compounds represent a new class of cytotoxic anti-tumor drugs.
Anti-mitotic and platinum derivatives anti-neoplastic agents are described in various scientific publications. The main representatives of the anti-mitotic class are: Paclitaxel, Docetaxel, Vinblastine, Vincristine, Vindesine and Vinorelbine; see for example the review: Cancer, Principles and Practice of Oncology, Lippincott-Raven Ed. (1997), 467-483. Platinum derivatives used in clinical practice are: CisPlatin, Carboplatin, Oxaliplatin, Nedaplatin and Lobaplatin; see review Cancer, Principles and Practice of Oncology, Lippincott-Raven Ed. (1997), 418-432.
4-Demethoxy-3xe2x80x2-deamino-3xe2x80x2-aziridinyl-4xe2x80x2-methansulfonyl daunorubicin is the preferred compound to be used in the present invention, more preferably in combination with oxaliplatin docetaxel or paclitaxel. The present invention also provides a product comprising an anthracycline of formula Ia or Ib as defined above and an anti-neoplastic anti-mitotic compound and/or a platinum derivative, as combined preparation for simultaneous, separate or sequential use in antitumor therapy.
A further aspect of the present invention is to provide a method of treating a mammal including humans, suffering from a neoplastic disease state comprising administering to said mammal an anthracycline of formula Ia or Ib as defined above and an anti-neoplastic anti-mitotic compound and/or a platinum derivative, in amounts effective to produce a synergetic anti-neoplastic effect.
The present invention also provides a method for lowering the side effects caused by anti-neoplastic therapy with an anti-neoplastic agent in mammals, including humans, in need thereof, the method comprising administering to said mammal a combination preparation comprising an anti-neoplastic anti-mitotic compound and/or a platinum derivative as defined above and an anthracycline of formula Ia or Ib, as defined above, in amounts effective to produce a synergistic anti-neoplastic effect.
By the term xe2x80x9ca synergistic anti-neoplastic effectxe2x80x9d as used herein is meant the inhibition of the growth tumor, preferably the complete regression of the tumor, administering an effective amount of the combination of an anthracycline of formula Ia or Ib as defined above and an anti-mitotic compound and/or a platinum derivative to mammals, including human.
By the term xe2x80x9cadministered xe2x80x9d or xe2x80x9cadministeringxe2x80x9d as used herein is meant parenteral and/or oral administration. By xe2x80x9cparenteralxe2x80x9d is meant intravenous, subcutaneous and intramuscolar administration. In the method of the subject invention, the anthracycline may be administered simultaneously with the compound with anti-mitotic activity, and/or a platinum derivative, or the compounds may be administered sequentially, in either order. It will be appreciated that the actual preferred method and order of administration will vary according to, inter alia, the particular formulation of the anthracycline of formula Ia or Ib being utilized, the particular formulation of the anti-mitotic compound, such as one of taxane analog class and of the platinum derivative being utilized, the particular tumor model being treated, and the particular host being treated
In the method of the subject invention, for the administration of the anthracycline of formula Ia or Ib, the course of therapy generally employed is from about 0.1 to about 200 mg/m2 of body surface area. More preferably, the course therapy employed is from about 1 to about 50 mg/m2 of body surface area.
In the method of the subject invention, for the administration of the anti-mitotic compounds the course of therapy generally employed is from about 1 to about 1000 mg/m2 of body surface area. More preferably, the course therapy employed is from about 10 to about 500 mg/m2 of body surface area.
In the method of the subject invention, for the administration of the platinum derivative the course of therapy generally employed is from about 1 to about 1000 mg/m2 of body surface area. More preferably, the course therapy employed is from about 100 to about 500 mg/m2 of body surface area. The anti-neoplastic therapy of the present invention is in particular suitable for treating breast, ovary, lung, colon, kidney, stomach, pancreas, liver, melanoma, leukemia and brain tumors in mammals, including humans.
In a further aspect, the present invention is directed to the preparation of a pharmaceutical composition containing an effective amount of an anthracycline of formula Ia or Ib as defined above and an anti-neoplastic anti-mitotic compound and/or a platinum derivative in the prevention or treatment of metastasis or for the treatment of tumors by angiogenesis inhibition, as well as to the use of an anthracycline of formula Ia or Ib as defined above and an anti-neoplastic anti-mitotic compound and/or a platinum derivative for the treatment of tumors by angiogenesis inhibition or for the treatment or prevention of metastasis.